Project Summary/Abstract People living with human immunodeficiency virus (HIV) infection are at increased cardiovascular disease (CVD) risk compared to those without HIV infection. CVD is a leading cause of death among people with HIV infection, however the factors that contribute to CVD in HIV disease are uncertain. Identifying contributors to CVD in HIV has been challenging because the HIV epidemic has evolved over the past 30 years in ways that affect CVD risk. Today, people living with HIV are diagnosed younger, treated earlier, use ART regimens with less metabolic toxicities, live longer and to older ages, and have a lower prevalence of cigarette smoking. Clinical CVD in HIV is characterized by a higher prevalence of type I myocardial infarctions with low CD4+ T- cell count and older era of ART treatment as risk factors. Type II myocardial infarctions also appear to be common in people with HIV disease and may occur with fewer traditional CVD risk factors. These observations suggest that treating traditional CVD risk factors alone will not suffice for preventing CVD events in people with HIV infection and emphasize the need to better understand the causes of CVD among people living HIV across the lifespan from childhood to older adulthood in order to better prevent CVD events. Flow-mediated dilation (FMD) and peak hyperemic flow velocity (PHRV) are ultrasound measures of arterial function that are associated with CVD risk factors and predict future CVD events. In persons with HIV, brachial artery FMD has been used to describe associations between HIV infection, its severity, its treatment, and CVD risk factors in children and adults. In 2008, the NHLBI standardized these measurements as part of its HIV- CVD Initiative with a broader goal of harmonizing data acquisition, lab and imaging endpoint measurements, data management, and statistical analysis in studies of CVD risk in HIV-infected persons. This novel initiative includes children with HIV, ART-nave HIV-infected adults, and ART-treated HIV infected adults, several of whom are older and highly ART-experienced. Using harmonized data from the HIV-CVD initiative enhanced by 4 large cohorts from the NIAID AIDS Clinical Trial Group and 2 cohorts of HIV-negative individuals each with harmonized laboratory and FMD measures, we will determine (i) the effects of measures of HIV disease severity and CVD risk factors on arterial function in persons living with HIV infection and if these effects are influenced by age, HIV suppression, antiretroviral therapy (ART) agents, ART duration, and sex; and (ii) if arterial function is worse among HIV-infected than -uninfected individuals using a novel statistical analyses, and if so, which measures of HIV-disease and severity and/or which CVD risk factors explain these differences. We will leverage previously acquired and harmonized data to characterize the effects of HIV infection, HIV disease severity, and CVD risk factors on validated measures of CVD risk and arterial dysfunction in men and women across a wide age range of people with HIV infection. Outcomes of this project may improve CVD risk prediction and targeting of CVD prevention interventions in people with HIV infection.